Hepatobiliary cancers, including hepatocellular carcinomas (HCC) and intrahepatic cholangiocarcinomas (iCCA), represent a major global health burden that continues to challenge biological researchers and clinicians alike. Hepatobiliary cancers are the second or third leading cause of cancer mortality worldwide, with over 840,000 new cases diagnosed in 2018. This Keystone Symposia meeting will be the first of its kind to focus specifically on this challenging disease. The meeting aims to integrate emerging basic and translational research with the clinical perspective, in order to advance our understanding of the pathobiology behind both HCC and iCCA, with the ultimate goal of guiding novel treatment and prevention strategies targeting these underlying mechanisms. The program will explore current challenges in the field, including (1) shifting etiological trends, focusing on mechanisms linked to cell injury, inflammation, and fibrogenesis; (2) roles of the microbiome and tumor microenvironment in affecting disease progression, therapeutic resistance, and immunosurveillance; (3) challenges of inter-and intra-tumoral heterogeneity; (4) identification of novel and more effective biomarker signatures for monitoring prognosis and treatments; (5) advances in “omics” for personalizing therapies; and (6) current and emerging trends in molecular and immune targeting. Moreover, this unique meeting is paired with a joint meeting on fatty liver disease, which is a perfect fit in lieu of the fact that non-alcoholic steatohepatitis is an important risk factor for hepatobiliary cancer. These joint meetings will foster new and productive research collaborations towards both basic and translational advances, as well as offer valuable training opportunities for basic researchers and clinician scientists.